Innate immunity drives pathogenesis of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the general population. This disease is characterized by persistent articular inflammation and joint damage driven by the proliferating synovial tissue fibroblasts as well as neutrophil, monocyte and lymphocyte trafficking into the synovium. The factors leading to RA pathogenesis remain poorly elucidated although genetic and environmental factors have been proposed to be the main contributors to RA. The majority of the early studies focused on the role of lymphocytes and adaptive immune responses in RA. However, in the past two decades, emerging studies showed that the innate immune system plays a critical role in the onset and progression of RA pathogenesis. Various innate immune cells including monocytes, macrophages and dendritic cells are involved in inflammatory responses seen in RA patients as well as in driving the activation of the adaptive immune system, which plays a major role in the later stages of the disease. Here we focus the discussion on the role of different innate immune cells and components in initiation and progression of RA. New therapeutic approaches targeting different inflammatory pathways and innate immune cells will be highlighted here. Recent emergence and the significant roles of innate lymphoid cells and inflammasomes will be also discussed.

Keywords: Cytokines; Inflammasomes; Inflammation; Innate immune system; Rheumatoid arthritis; Toll-like receptors.

Fig. 1

Contribution of various innate immune cells to RA pathogenesis. Monocytes, macrophages, dendritic cells, neutrophils, natural killer cells and innate lymphoid cells play a key role in the early stages as well as in the progression of rheumatoid arthritis. Figure was reated with BioRender.com.

Fig. 2

Innate immune signaling during in RA. Upon ligand binding, Toll-like receptors (TLR) and Interleukin-1 receptor (IL-1R) activate a series of intracellular signaling events that lead to the activation of distinct transcription factors, which culminate in the induction of gene transcription and subsequent secretion of various pro-inflammatory cytokines (e.g. TNF, IL-6, type I interferons (IFN)) and growth factors (e.g. GM-CSF). However, one of these cytokines, IL-1β, cannot be secreted unless it gets processed first by caspase-1. Caspase-1 itself is a zymogen and its activity requires the assembly of a molecular complex, called the inflammasome, which is activated when a danger signal has been sensed. Caspase-1 also cleaves gasdermin D (GSDMD) into two fragments (N and C terminus). The N-terminal fragment of GSDMD then oligomerize and form a pore in the plasma membrane, which allows for the release of active IL-1β and other cellular components. All these cytokines then act locally or systemically to promote an inflammatory status in the synovium and activate/attract various immune cells that initiate and contribute to RA pathogenesis. Figure was created with BioRender.com